Research Projects

This section introduces all current projects of the Systems Ecology group.

Human-microbe interactions in health and disease

Organismal and functional biogeography of the human gastrointestinal tract and its potential involvement in colorectal cancer

The human body is home to microbial communities whose member cells as well as genes outnumber our own. The largest part of the human microbiome resides in the gastrointestinal tract and it greatly influences human health and disease. Metagenomic DNA from faecal samples has been analysed in detail in recent years to understand the structure and function of the gastrointestinal microbiome. Links between colonization patterns and human well-being or disease have been identified. Here, we are using an integrated omics approach to identify potential links between gut microbial community structure and function, and colorectal cancers. In addition, differences/commonalities between the oral microbiome and the colonic microbiota are being analysed.

Collaborator: Peer Bork (European Molecular Biology Laboratory, Heidelberg, Germany)

Funding: FNR CORE grant "microCancer"  

Changes in the gastrointestinal microbiome and immune status during chemotherapy and immune ablative intervention in humans

Chemotherapeutic treatments for malignant diseases are known to greatly impact patients’ gastrointestinal tract (GIT) microbiomes. Resulting imbalances at the mucosal interface may culminate in mucositis, which is considered the major complication associated with chemotherapy and radiotherapy. A frequent adverse effect of allogeneic stem cell transplantation (allo-HSCT) potentially linked to the microbiome is graft-versus-host disease.

In this project, we are investigating changes in the composition of the GIT microbiome during and after different cancer treatment regimens and allo-HSCT. Specifically, we aim to correlate the detected shifts in the microbiome with development or amplification of treatment side effects and overall outcome. Ultimately, this could enable to identify patients at risk based on their specific GIT microbiome profile and to develop individually tailored treatments.

Collaborators: Norbert Graf, Arne Simon and Jörg Bittenbring (Saarland University Medical Center)

Funding: Internal Research Project of University of Luxembourg “ImMicroDyn” 

Diabetes multiplex family study (the MUST study)

Recent evidence from high-resolution molecular studies suggests links between microbial dysbiosis in the gastrointestinal tract and a number of complex chronic diseases including diabetes mellitus. The present study forms a pilot study for the larger Luxembourg-based Diabetes Multiplex Family Study (MUST). Within the pilot study, we investigate the interplay of the gastrointestinal microbiota, lifestyle and genetic background in an observational study of families with two or more individuals affected by type 1 diabetes mellitus. Faecal samples which have undergone comprehensive biomolecular extractions are currently analysed using a multi-omics approach. Anthropometric data, including demographics, medical history, health status, medication, and dietary habits of all study participants were collected and are integrated with molecular data.

Collaborators: Carine de Beaufort (LCSB), Karsten Hiller (TU Braunschweig) and Fay Betsou (Integrated BioBank of Luxembourg)

Reference: Heintz-Buschart A, May P, Laczny CC, Lebrun LA, Bellora C, Krishna A, Wampach L, Schneider JG, Hogan A, de Beaufort C, Wilmes P. Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes. Nature Microbiology 2016 Oct 10;2:16180. doi: 10.1038/nmicrobiol.2016.180

Colonisation, succession and evolution of the human gastrointestinal microbiome from birth to infancy (the COSMIC study)

Perturbations to the colonization process of the human gastrointestinal tract induced by caesarean section delivery have been suggested to result in adverse health effects later in life. Although much research has been performed on bacterial colonization and succession, much less is known about the other two domains of life, archaea and eukaryotes and their potential impact on neonatal health. Based on previous results, we observed that fundamental differences in the microbiome were observable as early as 3 days after birth between delivery modes (vaginal vs caesarean section delivery). However, more specific information on the earliest time after delivery and the potential transfer of neonatal colonizers from mother to infant is proportionally low to date.
In order to detect and analyze the colonization process over the first year of life in vaginally and caesarean section delivered infants, a longitudinally sampled study called Cosmic has been set up in Luxembourg. The study is divided into 2 subsections, one focussing on the colonization of the neonatal gastrointestinal microbiome by all 3 domains of life (bacteria, archaea and eukaryotes), while the follow-up study mainly targets the earliest colonization process and the potential transfer of neonatal colonizers from mother to infant using high-throughput techniques and specifically adapted methods to minimize the impact of potential contaminants.

Collaborators: Carine de Beaufort (CHL) ; Integrated BioBank of Luxembourg (IBBL)

Funding: FNR: AFR – Colonisation, succession and evolution of the human gastrointestinal microbiome in infants at high risk of metabolic disease in adulthood – COSMIC-PhD1; Fondation André et Henriette Losch

Non-invasive microbiome-derived multi-omic biomarkers for the early-stage detection and stratification of Parkinson’s disease (MiBiPa)

Parkinson’s disease (PD) is a neurodegenerative disease with characteristic motor symptoms that are commonly accompanied by pathological α-synuclein aggregation. Presently the propagation of α-synuclein aggregation in PD is proposed to start in the periphery, i.e. in the enteric nervous system and the olfactory bulb. Our study focuses on these two ports of entry for potential pathogenic agents in PD. We hypothesize that changes in microbial community structure and function in the gastrointestinal tract as well as the nasal cavity accompany PD from its onset, progression through its most specific prodrome REM sleep behaviour disorder (RBD) to manifest PD. We aim to (i) develop a microbiome biomarker model for Parkinson’s disease based on microbiome structural and functional signatures in faeces and/or nasal lavages, (ii) validate the biomarker, (iii) assess its applicability for early diagnosis of high-risk cohorts (such as RBD patients), and (iv) contribute to the understanding of the disease development by characterizing PD-specific microbiota. This is of particular relevance in relation to the development of future disease-modifying neuroprotective therapies that would require intervention at the earliest stages of disease but also to identify preventive strategies for PD.

Collaborators: Brit Mollenhauer (Paracelsus Elena Klinik Kassel, Germany), Wolfgang Oertel (Philipps-University Marburg)

Funding: pending.

Small RNA-mediated human-microbial cross-talk

The human gastrointestinal tract is densely colonized by several bacterial species, and imbalances in the microbiota influence human health. Bacteria are known to change expression of genes to cope with modified environments and bacterial sRNAs play crucial roles in such responses. Furthermore, several studies have postulated that bacterial sRNAs influence bacterial pathogenesis. In the present projects, we are characterising the functions of sRNAs (primarily exported sRNAs) which we have identified in the gastrointestinal tract and in enteric bacteria to understand whether these molecules may play roles in interspecies communication.

Collaborator: Esther N.M. Nolte-'t Hoen (Utrecht University, Dept Biochemistry & Cell Biology, Fac Veterinary Medicine, Netherlands); Julien Godet (Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, Faculté de Pharmacie)

References:

Ghosal A, Upadhyaya BB, Fritz JV, Heintz-Buschart A, Desai MS, Yusuf D, Huang D, Baumuratov A, Wang K, Galas D, Wilmes P. The extracellular RNA complement of Escherichia coli. Microbiologyopen. 2015 Jan 21. doi: 10.1002/mbo3.235. 

Joëlle V. Fritz; Extracellular RNA in Bacteria, http://exrna.org/extracellular-rna-bacteria/

Fritz, J. V., Heintz-Buschart, A., Ghosal, A., Wampach, L., Etheridge, A., Galas, D., & Wilmes, P. (2016). Sources and Functions of Extracellular Small RNAs in Human Circulation. Annual review of nutrition. doi:10.1146/annurev-nutr-071715-050711

Funding: BEaR FNR COREJunior programme grant

Eco-Systems Biology of Lipid Accumulating Organisms (LAOs) and biofilms

Genomics of isolated lipid accumulating bacteria

In this project we are reconstructing the genomes of bacteria isolated from our model wastewater lipid accumulating communities. The lack of genome sequences from appropriate reference organisms continues to hamper the integration of community-level multi-omic data (e.g., metagenomic, metatranscriptomic, metaproteomic, etc) from all but the most heavily studied microbial ecosystems. To address this limitation, we have sequenced the genome of Candidatus Microthrix parvicella, a model lipid-accumulating bacterium; and are working on sequencing that of 130 additional isolates. The genome sequences will help us improve our assembly and read-recruitment analyses of community sequence data. Coupled with phenotypic characterization of these organisms, they will also give us an insight into the biology of the dominant members of our model community.

Collaborators: Paul Keim and Lance Price (TGen North, Flagstaff, Arizona, USA)

Funding: FNR ATTRACT programme "SysBioNaMA"

Reference: Muller EEL, Pinel N, Gillece JD, Schupp JM, Price LB, Engelthaler DM, Levantesi C, Tandoi V, Luong K, Baliga NS, Korlach J, Keim PS, Wilmes P (2012) Genome Sequence of “Candidatus Microthrix parvicella” Bio17-1, a Long-Chain-Fatty-Acid-Accumulating Filamentous Actinobacterium from a Biological Wastewater Treatment Plant. Journal of Bacteriology 194:6670–6671. http://jb.asm.org/content/194/23/6670.abstract.

Integrated omics of wastewater lipid accumulating microbial consortia

In this project, we are characterizing microbial communities at the genomic and transcriptomic level, with a special interest on lipid accumulating bacterial populations, which are naturally enriched in biological wastewater treatment systems and may be harnessed for the conversion of mixed lipid substrates (wastewater) into biodiesel. We explicitly aim to elucidate the genetic blueprints and the functional relevance of specific populations within the community. We are focusing on within-population genetic and functional heterogeneity, trying to understand how fine-scale variations contribute to differing lipid accumulating phenotypes. Insights from this project will help us understand at a fundamental level the functioning of microbial ecosystems; and in a concrete level, help us improve optimization and modeling strategies for current and future biological wastewater treatment processes.

Collaborators: Paul Keim and Lance Price (TGen North, Flagstaff, Arizona, USA)

Funding: FNR ATTRACT programme "SysBioNaMA"; MetaLABpop FNR AFR PDR programme grant;

References:

Muller EE, Glaab E, May P, Vlassis N, Wilmes P (2013). Trends Microbiol 21:325-333.doi: 10.1016/j.tim.2013.04.009.

Muller EE, Pinel N, Laczny C, Hoopmann M, Narayanasamy S, Lebrun LA; Roume H, Lin J, May P, Hicks N, Buschart A, Wampach L, Liu C, Price L, Gillece J, Guignard C, Schupp J, Vlassis N, Baliga N, Moritz R, Keim P, Wilmes P (2014). Nature Communications 5:5603 doi:10.1038/ncomms6603

Roume, H., Heintz-Buschart, A., Muller, E. E. L., May, P., Satagopam, V. P., Laczny, C. C., et al. (2015). Comparative integrated omics: identification of key functionalities in microbial community-wide metabolic networks. npj Biofilms and Microbiomes, 1, 15007. doi:10.1038/npjbiofilms.2015.7

Spatiotemporal organisation during development of a bacterial biofilm

The spatial and temporal control of cell differentiation is crucial in all multicellular structures and tissues and even microbial communities such as biofilms. However, how cellular differentiation is regulated in space and time remains poorly understood. Experimental accessibility makes microbial biofilms a particularly suitable model system to study this problem. It is known that bacteria communicate within the biofilm and share tasks, as they differentiate into specialized cells.
The research aims to uncover fundamental principles that govern the spatial and temporal differentiation of cells within a structured biofilm community. Utilizing quantitative experiments can reveal when, where and how cells differentiate into distinct phenotypes during the self-organization of biofilms.

Funding: DFG Research Fellowship

Improving the bioleaching of chalcopyrite by multiscale modelling using meta-transcriptomics, meta-proteomics, and imaging data

Environmentally friendly techniques, such as biomining, must be developed to meet the increased European demand for metals. Biomining exploits acidophilic microorganisms for the recovery of metals from sulphide ores in tanks, heaps and dumps. In this project, biofilm formation of moderately thermophilic bioleaching bacteria, Acidithiobacillus caldus, Leptospirillum ferriphilum and Sulfobacillus thermosulfidooxidans on chalcopyrite surfaces will be studied with the aim to improve leaching of copper from the mineral. Since a unique feature of the experimental setup is the use of well-defined microbial communities of limited diversity and known cultivation conditions, it will be possible to establish and test novel approaches for measuring and modelling a mixed-microorganism biofilm formation process.

Collaborators: Mark Dopson, Stephan Christel (Linneaus University Kalmar), Ansgar Poetsch (Ruhr Universitaet Bochum), Wolfgang Sand, Mario Vera (Universitaet Duisburg Essen), Igor Pivkin, Antoine Buetti-Dinh (Università della Svizzera italiana)

Funding: EU ERASysApp grant “SysMetEx”

Comparative integrated omic analysis of community-wide metabolic processes

The project aims to elucidate details of the fate of lipids within mixed microbial communities present at the surface of an anoxic activated sludge wastewater treatment system, in view of potentially harnessing these traits for direct production of biodiesel from wastewater. However, such mixed microbial communities exhibit extensive complex and various interactions and we still know very little about their overall functional capacity. In this project, we use a unique framework for comparative eco-systems biology in which we integrate multi-omics data including metagenomic, metatranscriptomic, metaproteomic and metabolomic information into a community-level metabolic network reconstruction. The mapping of the multi-omic information on the network allows us to identify key genes involved in conferring the community-wide lipid accumulation phenotype. The developed approach is further applicable to other microbial communities for which dynamic omic data exists

Funding: FNR ATTRACT programme grant ”SysMetEx”; SysBioWwTBioEng FNR AFR PHD programme grant

Biomarkers for assessing the performance of anaerobic digestion processes

Advances towards efficiency improvement of the anaerobic digestion process (AD) for biogas production is often quoted to be dependent on two major key subjects of research (1) an in depth understanding of the structure and dynamics of the microbial populations involved in the process and (2) the development of on-line monitoring tools to better predict process dysfunction occurring during inadequate organic loading rate. We are applying our integrated omics methodology to obtain detailed insights into the microbial ecology and microbial community dynamics of the anaerobic digestion process in relation to reactor design and feeding regime. We hope to identify biomarkers which will prove helpful for real-time performance monitoring of AD plants.

Collaborator: Philippe Delfosse (Centre de Recherche Public – Gabriel Lippmann, Belvaux, Luxembourg)

Funding: FNR CORE programme grant “GASPOP”

Methods

Sequencing facility

We are currently hosting the LCSB sequencing facility equipped with Illumina MiSeq and NextSeq sequencers. With these sequencers we can implement very broad range of protocols encompassing Genomics (metagenomics, amplicon sequencing, RRBS, ChIP/MeDIP sequencing and single cell genomics) and Transcriptomics (metatranscriptomics, 16s/18s rRNA sequencing, targeted RNA sequencing, stranded RNA transcriptomics, single cell transcriptomics, small RNA sequencing and RNA exome capture). We work closely with the LCSB bioinformatics core team, which gives us the advantage in in-depth data processing and analysis

 

Comprehensive biomolecular isolation for integrated omics

Isolation and characterisation of lipid accumulating bacteria

We are building a culture collection of lipid accumulating bacteria isolated from biological wastewater treatment plants under various different culture conditions. Isolates are screened for the lipid accumulation phenotype before undergoing whole genome sequencing. 600 isolates have been obtained so far which are currently undergoing in-depth characterization.

Funding: FNR ATTRACT programme grant “SysBioNaMA”; MetaLABpop FNR AFR PDR programme grant

Comprehensive biomolecular isolation protocol

In microbial ecology, high-resolution molecular biology approaches are vital for discovering and characterizing the vast microbial diversity, and understanding the interaction of microbial communities with biotic and abiotic environmental factors. Integrated omics, comprising community genomics, transcriptomics, proteomics and metabolomics, is able to reveal the links between genetic potential and functionality in microbial communities in a truly systematic fashion. However, mixed microbial communities are complex, dynamic and heterogeneous and it is therefore essential that biomolecular fractions obtained for high-throughput omic analyses are representative of single undivided samples to facilitate meaningful data integration, analysis and modelling. We have developed a new methodological framework for the reproducible sequential isolation of high-quality polar and non-polar metabolites polar and non-polar, RNA (optionally split into large and small RNA fractions), DNA and proteins from single undivided mixed microbial community samples. The developed methodological framework lays the foundation for standardized molecular eco-systematic studies on a range of different microbial communities in the future.

Funding: FNR ATTRACT programme grant “SysBioNaMA”; SysBioWwTBioEng FNR AFR PHD programme grant; MetaLABpop FNR AFR PDR programme grant; European Union Joint Programme – Neurodegenerative Disease Research grant

References:

Roume H, EL Muller E, Cordes T, Renaut J, Hiller K & Wilmes P (2013) A biomolecular isolation framework for eco-systems biology. ISME J 7: 110–121. http://dx.doi.org/10.1038/ismej.2012.72.

Roume H, Heintz-Buschart A, Muller EE, & Wilmes P (2013) Sequential isolation of metabolites, RNA, DNA, and proteins from the same unique sample. Methods Enzymol 531: 219-236.doi: 10.1016/B978-0-12-407863-5.00011-3.

Muller EE, Heintz-Buschart A, Roume H, Wilmes P (2013) The sequential isolation of metabolites, RNA, DNA, and proteins from a single, undivided mixed microbial community sample. Protocol Exchange doi:10.1038/protex.2014.051.

Pranjul S, Muller EE, Lebrun LA, Wampach L, Wilmes P (submitted) Sequential isolation of DNA, RNA, protein and metabolite fractions from murine organs and intestinal contents for integrated omics of host-microbiota interactions. Methods in Molecular Biology.

High-throughput comprehensive biomolecular extractions for integrated omic analysis of biological samples

Integrated omic analysis of biological samples aims to resolve the information within each biomolecular fraction from genetic potential of the organisms to their functional capacity. Our comprehensive biomolecular isolation protocol lays the foundation for systematic integrated omics. The protocol itself is time consuming and therefore throughput is mediocre. Consequently, we are investigating approaches for automation of the biomolecular extraction protocol to improve throughput and provide a platform for standardized integrated omic analyses of different biological samples in the future.

Funding: FNR ATTRACT programme grant “SysBioNaMA”; MetaLABpop FNR AFR PDR programme grant; European Union Joint Programme – Neurodegenerative Disease Research grant  

Contaminant-free sRNA sequencing

Comprehensive analyses of biomolecules from low input samples, for example sRNAseq from human plasma samples, are prone to distortion by different biases. The danger of contamination with biomaterial from lab reagents is imminent. In this project, we develop strategies to control the cleanness of lab reagents and to improve the safety of commonly used extraction kits.

Collaboration: David Galas (Pacific Northwest Diabetes Research Institute, Seattle, USA), Qiagen  

Bioinformatic approaches for integrated community omics

Binning of metagenomic sequences using nucleotide signatures and machine learning approaches

Any environmental sample, including those taken from human subjects (e.g. from the gastrointestinal tract) contain a complex mixture of microbial organisms. Due to current limitations of isolated culturing of many of these organisms, community genomics are generally used to study microbial consortia in situ. However, the scrambled genomic information obtainable using metagenomics needs to be related back to the organisms of origin, i.e. binned, so as to be able to study the individual community members sepatately. The advent of next-generation sequencing allows to create very large data sets, hence further increasing the difficulty of processing these complex mixtures. The goal of this computational biology project is to use in silico approaches for the retrieval of the individual sequences of the constituent organisms in an efficient, precise and automated way using state-of-the-art machine learning approaches. Downstream applications (e.g. genomic assembly and multi-omics integration) will benefit from this step by, among others, reducing the complexity, increasing sensitivity and allowing for parallel workflows.

Funding: DissRNA FNR AFR PHD programme grant (to Cédric Laczny)

References:

Laczny, C. C., Pinel, N., Vlassis, N., & Wilmes, P. (2014). Alignment-free visualization of metagenomic data by nonlinear dimension reduction. Scientific reports, 4, 4516. doi:10.1038/srep04516

Laczny, C. C., Sternal, T., Plugaru, V., Gawron, P., Atashpendar, A., Margossian, H. H., et al. (2015). VizBin - an application for reference-independent visualization and human-augmented binning of metagenomic data. Microbiome, 3(1), 1. doi:10.1186/s40168-014-0066-1

Laczny, C. C., Muller, E. E. L., Heintz-Buschart, A., Herold, M., Lebrun, L. A., Hogan, A., et al. (2016). Identification, Recovery, and Refinement of Hitherto Undescribed Population-Level Genomes from the Human Gastrointestinal Tract. Frontiers in microbiology, 7(75), 533. doi:10.1089/10665270050081478

Integrated omics data analysis pipeline

Molecular Eco-Systems Biology generates massive omics datasets derived from next generation sequencing and high-throughput mass spectrometry. This data has to be filtered, processed and analysed in an integrated fashion. We are developing methods which allow integration of metagenomic, metatranscriptomic, metaproteomic and metabolomic data by combining efficient in-house pipelines together with state-of-the-art publicly available software tools.

Funding: FNR ATTRACT programme grant “SysBioNaMA”; FNR AFR PHD programme grant to Shaman Narayanasamy

References:

Narayanasamy S, Jarosz Y, Muller EE, Heintz-Buschart A, Herold M, Kaysen A, Laczny CC, Pinel N, May P, Wilmes P. IMP: a pipeline for reproducible reference-independent integrated metagenomic and metatranscriptomic analyses. Genome Biol. 2016 Dec 16;17(1):260. DOI: 10.1186/s13059-016-1116-8

Human-microbe co-culture models

Design, fabrication and implementation of a microfluidics-based human-microbial in vitro co-culture device

In the natural world, individual cell populations are typically not found in isolation but are in direct contact with other cell types or organisms. Co-culture systems have been developed for addressing a number of fundamental biological questions relating to interactions between different cell populations but are typically limited in scope. This project is focussed on the development of a modular microfluidics-based co-culture device, termed HuMiX, which allows proximal co-culture of human epithelial cells and microbes. The HuMiX device mimics physiologically relevant spatial dimensions and establishes extracellular matrix conditions, which allow the establishment of stable growth conditions for both cell contingents. We have developed such devices from design to implementation via state-of-the-art micro fabrication techniques. The devices include integrated sensors for online monitoring of physicochemical parameters like concentration of oxygen and pH. As a proof-of-concept, we have recently demonstrated long-term co-culture of human epithelial cell lines (Caco2) with LGG and/or B.caccae,, which forms the basis for developing a microfluidics-based model of the entire human gastrointestinal tract.

Collaborator: Frederic Zenhausern (University of Arizona, Phoenix, USA)

Funding: FNR CORE programme grant ”HuMiX”; Proof-of-concept FNR programme grant “HuMix2.0”

References:

Fritz J.V., Desai M.S., Shah P., Schneider J.G., Wilmes P. (2013) From meta-omics to causality: experimental models for human microbiome research. Microbiome 1(1):14. doi:10.1186/2049-2618-1-14

Shah P, Fritz JV, Glaab E, Desai MS, Greenhalgh K, Frachet A, Niegowska M, Estes M, Jäger C, Seguin-Devaux C, Zenhausern F, Wilmes P. A microfluidics-based in vitro model of the gastrointestinal human-microbe interface. Nat Commun. 2016 May 11;7:11535. doi: 10.1038/ncomms11535

Co-culture of human primary cells with gastrointestinal microorganisms

A human individual’s microbiome consists of around 100 trillion cells, which represents at least ten times as many cells as human cells constitute the body. Beneficial effects of the presence of microbial communities on human physiology range from immune cell development and homeostasis, food digestion via the fermentation of non-digestible dietary components in the large intestine to balancing the host’s metabolism and promoting angiogenesis. Negative consequences for the host linked to the human microbiome include for example chronic inflammation and infection. Indeed, shifts in microbial community structure and function (dysbiosis) have been linked to numerous human diseases, including inflammatory bowel disease, diabetes mellitus, obesity, cardiovascular disease and cancer. The largest microbial reservoir of the human body is the gastrointestinal tract (GIT) and, thus, it is also the most studied and important from a biomedical perspective.

Therefore, it seems of great importance to understand and control the interplay between GIT microorganisms and human immune cells located in the gastrointestinal-associated lymphoid tissue (GALT), which constitutes the largest immune compartment in the human body. It is estimated that T cells associated with the small intestinal epithelium alone account for more than 60% of the total body lymphocytes. Currently, it is difficult to study the crosstalk between human immune cells and GI microorganisms in vivo in humans for obvious ethical reasons. Moreover, a systematic manipulation of variables to test the impact of a specific subtype of immune cells on the microbiota as well as the inflammatory effect of specific microbial species on human immune cells is not possible in vivo. In this respect, we plan to develop a microfluidics-based in vitro co-culture system, which allows the culture and modulation of different subtypes of primary immune cells in presence and absence of human gut microorganisms. Bacterial and human immune cells are separated by an epithelial cell monolayer in order to closely mimic the GIT.

Funding: FNR: AFR - Development and establishment of a microfluidics-based in vitro culture model to study the impact of HIV infection on the gastrointestinal mucosal barrier - grant to Joëlle Fritz; FNR CORE programme grant, Proof-of-concept FNR programme grant

Collaborators: RIKEN Center for Integrative Medical Sciences, Laboratory for Gut Homeostasis, Team Leader: Kenya Honda

References:

Fritz JV, Desai MS, Shah P, Schneider JG, Wilmes P (2013). From meta-omics to causality: experimental models for human microbiome research. Microbiome 1(1):14. doi: 10.1186/2049-2618-1-14

Shah P, Fritz JV, Glaab E, Desai MS, Greenhalgh K, Frachet A, Niegowska M, Estes M, Jäger C, Seguin-Devaux C, Zenhausern F, Wilmes P. A microfluidics-based in vitro model of the gastrointestinal human-microbe interface. Nat Commun. 2016 May 11;7:11535. doi: 10.1038/ncomms11535.

A study of the molecular mechanisms underlying the response of human colorectal adenocarcinoma enterocytes to prebiotics/probiotics

The majority of the microorganisms constituting the human microbiome inhabit the gastrointestinal tract (GIT) where they play essential roles in governing human health. A variety of diseases including colorectal cancer (CRC) are associated with dysbiosis, a pathological imbalance in the intestinal microbiota. Apart from endogenous microbial consortia, diets supplemented with prebiotics, are thought to have a major effect on GIT microbiota and are inversely correlated with the risk of developing CRC. Furthermore, the use of probiotics including Lactobacillus rhamnosus GG has been found to exhibit anti-cancer effects. Here, we study the synergistic effects of probiotic bacterial strains, dietary components and colorectal adenocarcinoma enterocytes of the human GIT using the microfluidics-based GIT co-culture model (HuMiX). More specifically we are interested in the phenotypical characteristics of the enterocytes using specific cell invasion, migration and proliferation assays. We are also studying the gene expression changes in human enterocytes after different pre-and probiotic treatments within the HuMiX model.

A thorough mechanistic understanding of the interplay between dietary habits, bacterial metabolism and human physiology is required to understand the role of pre-and probiotics and apply them appropriately in CRC therapies and prevention. In this context, this project will likely results in recommendations for dietary and probiotic-based interventions to modulate the microbiota-host relationship in order to reduce the expression of pro- carcinogenic genes and reduce pro-inflammatory responses that have been found to play a pivotal role in CRC.

Collaborators: Serge Haan and Elisabeth Letelier(Life Sciences Research Unit, Luxembourg)

Funding: Internal Research Project of the University of Luxembourg “MiDiCa”; FNR AFR PhD grant to Kacy Greenhalgh and grant from the Luxembourg Personalised Medicine Consortium

Study of human−microbial molecular interactions using a model microbial community representative of the gastrointestinal tract

The microbial communities that inhabit the human gastrointestinal tract play roles in both health and disease. Different species of gut bacteria (~103) possess wider metabolic capabilities, including those not encoded in the human genome e.g., degradation of complex carbohydrates present in our diets. Changes in the relative proportions of distinct functional groups of gut bacteria, termed dysbiosis, have been implicated in several intestinal disorders, including diabetes, inflammatory bowel disease (IBD) and colon cancer. Little is known about the mechanisms behind dysbiosis; most studies have taken case-control comparative analytical approaches to identify species with altered abundance during disease. However, most studies have not had the statistical power to infer causal relationships. Therefore, in vivo or in vitro experiments are necessary to examine the effects of different bacterial groups. To carry out such experiments, it is necessary to compile representative artificial gut microbial communities with which hypotheses can be tested. Therefore, we have designed a synthetic (simplified) human intestinal microbiota that contains species with diverse metabolic potentials. This artificial microbiota is being used to study the interaction of gut microbes with the host, using in vivo (gnotobiotic mice) and in vitro (microfluidics-based device; see the section on HuMiX) approaches.

Funding: HuMiX FNR CORE programme grant